Glioblastoma (GBM) is a high-grade astrocytoma and represents the most common form of primary brain tumor in humans. The successful treatment of patients with GBM is still a major challenge with a median survival rate of 14.5 months after diagnosis (Stupp et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N Engl J Med 352: 987-996, 2005).
Interleukin 13 receptor alpha 2 (IL-13RA2) is richly over-expressed in GBM (Debinski et al., Human glioma cells overexpress receptor for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin. Clin Cancer Res 1: 1253-1258, 1995; Debinski et al., Receptor for interleukin 13 is a marker and therapeutic target for human high grade gliomas. Clin Cancer Res 5: 985-990, 1999; Mintz et al., IL13Rα2 is a glioma-restricted receptor for IL13. Neoplasia 4: 388-399, 2002). This receptor is different from the physiological receptor for IL-13 (IL-4A/IL-13RA1 heterodimer), because it is a monomer and binds only IL-13, and not IL-4, its homologue (Debinski, An immune regulatory cytokine receptor and glioblastoma multiforme: an unexpected link. Crit Rev Oncog 9: 255-268, 1998). IL-13RA2 belongs to a group of cancer/testis like tumor antigens (Debinski and Gibo, Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med 6: 440-449, 2000) and is one of the downstream gene targets following activation of both wild type EGFR and mutant EGFRvIII (Hu et al., Cytokine up-regulation of IL-13Rα2 in GBM cells leads to an increased potency of recombinant IL13 cytotoxin. Cancer Therapy 3: 531-542, 2005; Lal et al., Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res 62: 3335-3339, 2002). Demethylation causes up-regulation of IL-13RA2 suggesting epigenetic mechanisms are also involved in IL-13RA2 receptor regulation (Mintz and Debinski, Cancer genetics/epigenetics and the X chromosome: Possible new links for malignant glioma pathogenesis and immune-based therapies. Critic Rev Oncogen 11: 77-95, 2000) in addition to activation of PI3K and ERK pathways (Hu et al., Cytokine up-regulation of IL-13Rα2 in GBM cells leads to an increased potency of recombinant IL13 cytotoxin. Cancer Therapy 3: 531-542, 2005).
Several molecular therapies targeting IL-13Rα2 have been generated and all have the potential of being applied to management of patients with GBM. Among them are vaccines (Okano et al., Identification of a novel HLA-A*0201-restricted, cytotoxic T lymphocyte epitope in a human glioma-associated antigen, interleukin 13 receptor α2 chain. Clin Cancer Res 8: 2851-2855, 2002; Mintz et al., Protein and DNA-based active immunotherapy targeting interleukin 13 receptor alpha 2. Cancer Biother and Radiopharm 23: 581-589, 2008), re-targeted cytotoxic T cells (Kahlon et al., Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res 64:9160-9167, 2004) and new rationally designed IL-13 based cytotoxins (Chunbin et al., Targeting glioblastoma multiforme with an IL-13/diphtheria toxin fusion protein in vitro and in vivo in nude mice. Prot Engin 15: 419-427, 2002; Debinski et al., Novel anti-brain tumor cytotoxins specific for cancer cells. Nature Biotech 16: 449-453, 1998; Mintz et al., Molecular targeting with recombinant cytotoxins of interleukin-13 receptor alpha-2-expressing glioma. J Neuro-Oncol 64: 117-123, 2003). Additionally, novel IL-13RA2-targeted adenoviral and herpes virus constructs have been developed and could potentially be used as gene therapy vectors for the treatment of gliomas (Zhou et al., Genetic engineering of a herpes virus 1 vector dependent on the IL-13Rα2 receptor for entry into cells: interaction of glycoprotein D with its receptors is independent of the fusion of the envelope and the plasma membrane. Proc Natl Acad Sci 99: 15124-15129, 2002; Ulasov et al., Novel recombinant adenoviral vector that targets the interleukin-13 receptor alpha2 chain permits effective gene transfer to malignant glioma. Hum Gene Ther 18: 118-129, 2007; Candolfi et al., Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proc Natl Acad Sci 107: 20021-20026, 2010). Thus, IL-13RA2 is a truly attractive molecular target, being over-expressed in a majority of, but not all, patients with GBM (Wykosky et al., IL-13 Receptor alpha-2, EphA2, and Fra-1 as molecular denominators of high-grade astrocytomas and specific targets for combinatorial therapy. Clin. Cancer Res 14: 199-208, 2008).
IL-13RA2 is also overexpressed in a variety of peripheral tumors, such as pancreatic cancer, gastric cancer, head and neck cancer, etc., and has been implicated in tumor metastasis.